BRAF status and mitogen-activated protein/extracellular signal-regulated kinase kinase 1/2 activity indicate sensitivity of melanoma cells to anthrax lethal toxin
BRAF status and mitogen-activated protein/extracellular signal-regulated kinase kinase 1/2 activity indicate sensitivity of melanoma cells to anthrax lethal toxin
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DOI：
10.1158/1535-7163.mct-05-0145
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发表时间：
2005-09-01
影响因子：
5.7
通讯作者：
Frankel, AE
中科院分区：
文献类型：
--
作者：
Abi-Habib, RJ;Urieto, JO;Frankel, AE
由保护性抗原和致死因子组成的炭疽致死毒素对人黑色素瘤细胞系和正常人细胞进行了细胞毒试验。18株黑色素瘤细胞系中有11株对炭疽致死毒素敏感（IC 50 < 400 pmol/L），其中10株携带V599 E BRAF突变。大多数正常细胞（10/15）对炭疽致死毒素不敏感，只有5/15正常人细胞对炭疽致死毒素敏感（IC_（50）< 400 pmol/L）。这些细胞包括单核细胞和内皮细胞的子集。在黑色素瘤细胞系和正常细胞中，炭疽毒素受体表达水平与炭疽致死毒素细胞毒性无关。此外，当用炭疽毒素受体转染时，炭疽毒素受体缺陷细胞系（PR 230）没有显示出对炭疽致死毒素的任何增强的敏感性。炭疽致死毒素毒性与黑色素瘤细胞系和正常细胞中促分裂原活化蛋白/细胞外信号调节激酶激酶（MEK）1/2磷酸化水平升高相关。炭疽致死毒素敏感的黑色素瘤细胞系和正常细胞具有比炭疽致死毒素抗性黑色素瘤细胞系和正常组织类型更高的磷酸-MEK 1/2水平。特异性MEK 1/2抑制剂UO 126对炭疽致死毒素耐药黑色素瘤细胞系无毒性，但对11个炭疽致死毒素敏感细胞系中的8个有毒性。这些结果表明，炭疽致死毒素毒性与活性MEK 1/2途径的水平升高相关，但与正常和恶性组织中的炭疽毒素受体表达水平无关。炭疽致死毒素可能是黑色素瘤患者的有用治疗剂，特别是那些携带V599 E BRAF突变并具有促分裂原活化蛋白激酶途径的组成型活化的患者。
Anthrax lethal toxin, composed of protective antigen and lethal factor, was tested for cytotoxicity to human melanoma cell lines and normal human cells. Eleven of 18 melanoma cell lines were sensitive to anthrax lethal toxin (IC50 < 400 pmol/L) and 10 of these 11 sensitive cell lines carried the V599E BRAF mutation. Most normal cell types (10 of 15) were not sensitive to anthrax lethal toxin and only 5 of 15 normal human cell types were sensitive to anthrax lethal toxin (IC50 < 400 pmol/L). These cells included monocytes and a subset of endothelial cells. In both melanoma cell lines and normal cells, anthrax toxin receptor expression levels did not correlate with anthrax lethal toxin cytotoxicity. Furthermore, an anthrax toxin receptor -deficient cell line (PR230) did not show any enhanced sensitivity to anthrax lethal toxin when transfected with anthrax toxin receptor. Anthrax lethal toxin toxicity correlated with elevated phosphorylation levels of mitogen -activated protein/extracellular signal-regulated kinase kinase [MEK) 1/2 in both melanoma cell lines and normal cells. Anthrax lethal toxin -sensitive melanoma cell lines and normal cells had higher phospho-MEK1/2 levels than anthrax lethal toxin-resistant melanoma cell lines and normal tissue types. UO126, a specific MEK1/2 inhibitor, was not toxic to anthrax lethal toxin resistant melanoma cell lines but was toxic to 8 of 11 anthrax lethal toxin-sensitive cell lines. These results show that anthrax lethal toxin toxicity correlates with elevated levels of active MEK1/2 pathway but not with anthrax toxin receptor expression levels in both normal and malignant tissues. Anthrax lethal toxin may be a useful therapeutic for melanoma patients, especially those carrying the V599E BRAF mutation with constitutive activation of the mitogen -activated protein kinase pathway.